Drug delivery device

ABSTRACT

Electrical treatment apparatus ( 100 ) for use with an associated molecule source, comprising: at least one electrode ( 106 ); a power source ( 120 ) for electrifying said at least one electrode; and a controller, which is programmed to activate the power source ( 120 ) to selectively electrify said at least one electrode ( 106 ) to apply at least one electric field including a transport effect for transporting a molecule in a desired manner and a non-excitatory control effect for controlling the activity of at least a part of a non-cardiac excitable tissue, said programming selected to achieve a desired provision of said molecule into said at least a part of an excitable tissue or associated vasculature, said desired provision being at least assisted by an interaction between the transport effect and the control effect.

FIELD OF THE INVENTION

[0001] The present invention relates to electrically mediated transportof drugs into cardiac tissue and/or into cells of the tissues.

BACKGROUND OF THE INVENTION

[0002] Electroporation is a technique used for introducing moleculesacross a cell membrane and into a cell. In a typical application, anin-vitro cell culture is mixed with a target molecule and a briefelectrical field is applied to the mixture. The electrical field causesa transient porosity of the cell membranes, allowing the molecules toenter the cell. U.S. Pat. No. 5,501,662, the disclosure of which isincorporated herein by reference, describes an electroporation systemfor blood, in which an electric field is applied to a vessel havingblood cells mixed with a target gene (or other molecules) and theelectric field causes the genes to be transported into the cells.Electroporation is especially useful for large molecules, such asproteins, and for other molecules which do not have a biologicalmechanism for crossing the cell barrier.

[0003] Iontophoresis is a method of transporting drugs into a bodytissue, from outside the body tissue, usually from the skin. The drug isprovided in a charged form and, when an electric field is applied, theelectric field moves the charged drug along the gradient of the field.

[0004] PCT publication WO98/15317, the disclosure of which isincorporated herein by reference, describes an implantable drug-elutingtip which uses a cardiac pacing signal to cause charged drug particlesto leave a reservoir and be available locally. It is suggested in thatpublication that the electric field of the pacing signal is sufficientto iontophorese the drug into the heart tissue. Injection of DNA intoindividual cells is suggested using a similar device, for apply toxinsto tumor cells, apparently not in the heart. However, it is not clearwhether the fields strengths and durations of a pacing signal aresufficient for electroporation or even iontophoresis for anyconsiderable depth.

[0005] U.S. Pat. No. 5,865,787, the disclosure of which is incorporatedherein by reference describes a catheter for electroporation oriontophoresis, in which the iontophoresis pulses are applied inconjunction with active pacing.

[0006] U.S. Pat. No. 5,387,419, the disclosure of which is incorporatedherein by reference, describes a system for controlled release ofantiarrhythmic agents.

SUMMARY OF THE INVENTION

[0007] One aspect of some exemplary embodiments of the invention relatesto using a non-excitatory pulse to control molecule availability at ornear excitable tissue, such as the heart, the uterus or the GI tract,which might be activated in an undesirable manner by an applied electricfield. The exerted control may include, for example, one or more ofcausing a molecule to exit a reservoir, iontophoresis of the moleculeinto tissues, release of the molecule from a circulating reservoir, suchas electrically-opened liposomes and/or electroporation of the moleculeinto individual tissue cells. An optional second non-excitatory pulsemay be provided to interact with the first pulse (e.g., to control thetissue) and/or the molecule. In some embodiments of the invention, themolecule availability pulse is excitatory and adverse effects of thepulse are prevented by the second pulse.

[0008] As used herein the term “non-excitatory pulse” means an appliedelectric field which does not induce an additional propagating actionpotential in the heart (or other relevant excitable tissue), for exampledue to its frequency, polarity, waveform, duration, amplitude and/or itsbeing applied at a time in the electrical activation cycle when thenearby tissue does not respond to the pulse.

[0009] As used herein the term molecule means any type of molecule,including, especially, genetic material, such as DNA and RNA, geneticvectors, such as viruses and plasmids, polypeptides, hormones and smallmolecule drugs. In addition, the molecules may include ATP, cAMP and/orparticles having the molecule adsorbed thereto or located inside avolume of a hollow particle, such as a liposome, which can betransported into the tissue or trapped in a matrix, such as a hydrogelmatrix reservoir on the electrode. Exemplary pharmaceuticals include:β-Blockers, anti-cancer drugs, specific antibodies, SERCA, VEGF andNitro components such as Nitroglycerine. In particular, some moleculesmay have a systemic toxic effect and/or may damage some organs of thebody. In another example, the provided molecule is an antagonist for adifferent molecule, also present in the body, for example antagonistse.g. Protamine which antagonizes Heparin.

[0010] In an exemplary embodiment of the invention, knowledge of whattypes of pulses will not cause an ectopic excitation and or otherarrhythmia, (herein referred to as an arrhythmia) in any particularexcitable tissue organ and/or methods for controlling such arrhythmiashould they occur are used to apply pulses having larger voltages,currents and/or durations than previously thought possible, to theexcitable tissue, for the purpose of transporting drugs. In addition, avariety of waveforms becomes available. Optionally, apparatus designedfor non-excitatory pulses is used (e.g., not a pacemaker), makingpossible various programmable pulse forms and larger amounts of power.However, in some embodiments of the invention, a modifiedpacemaker/simulator may be used, for example a pacemaker with modifiedprogramming, to provide a non-excitatory pulse.

[0011] Various types of electrodes may be used. In an exemplaryembodiment of the invention the type of electrode used is a pointelectrode. Alternatively or additionally, a line electrode, a wide areaelectrode, a vascular electrode which is inserted into a vessel and/or aone- or two-dimensional matrix electrode may be used.

[0012] In an exemplary embodiment of the invention, the molecules areprovided by the electrode, for example using a drug-eluting electrode ofone of various types as known in the art. Alternatively or additionally,the molecule is provided in other ways. For example the molecule isinjected systemically or locally or applied using an implanted pump(possibly with output ports at the region to be treated or in a vascularbed thereof or adjacent thereto where the electrical pulse can transportit). Possibly, a decomposing or other matrix having the moleculeembedded therein is used to supply the molecule. Alternatively, themolecule is ingested, inhaled or applied topically. In some cases, aplurality of molecules and/or molecule provision methods are usedsimultaneously in a single patient, for example both systemic and localprovision of two different molecules. Optionally, such two or moremolecules may interact, for example the local molecule blocking theactivity of the systemic one or enhancing it, or vice versa, forexample, the systemic molecule blocking the effect of the local moleculeoutside of the targeted area, where the concentration of the localmolecule is lower.

[0013] An aspect of some embodiments of the invention relates to aninteraction between non-excitatory signals applied and the moleculetransport. In some embodiments of the invention, the transport pulseand/or an optionally provided second non-excitatory pulse prevent and/orcounteract adverse affects of the transport pulse and/or of thetransported molecule, for example by preventing the propagation ofundesirable action potentials. In some embodiments of the invention, thetransport pulse is applied at a location spatially displaced from thelocation of the second non-excitatory pulse. In some embodiments of theinvention, the adverse effect that is contracted by the secondnon-excitatory pulse is caused by a non-transport electrical signal, forexample an electrical or optical signal used to stimulate cells in ornear the excitable tissue to perform angiogenesis.

[0014] In an exemplary embodiment of the invention the molecule and thenon-excitatory signal cooperate to have a desired, synergistic effect onthe excitable tissue, for example the molecule enhancing a contractilityincreasing effect of the signal or the signal enhancing a contractilityincreasing effect of the molecule. Alternatively, the signal may beselected to have a minimal (e.g., functional and/or sensory) effect onthe excitable tissue.

[0015] Various types of molecules may be used in exemplary embodimentsof the invention. In some particular embodiments of the invention,non-ionized/charged molecules are used for electrically mediatedtransport in the excitable tissue. Optionally, the effect ofelectroporation is achieved by the electric field of the non-excitatorysignal momentarily opening pores in the cardiac cell membranes.Alternatively or additionally, dipole charges are formed on themolecules, for transport, by using suitable electric field frequencies.In some embodiments, required field intensities, waveforms orfrequencies are provided by virtue of using non-excitatory fields.

[0016] An aspect of some exemplary embodiments of the invention relatesto a method of treating a dysfunction in an excitable organ. In anexemplary embodiment of the invention, a patient is temporarilyconnected to a device that electrically transports molecules intoexcitable tissue. Possibly, the device also performs monitoringfunctions and/or provides other treatment, such as applying electricalfields that prevent arrhythmia or pacing the excitable tissue.

[0017] An aspect of some exemplary embodiments of the invention relatesto treating coronary blood vessels or other blood vessels that are nearor inside the heart or other excitable tissue, using electricallymediated molecule transport. In an exemplary embodiment of theinvention, the timing and/or other parameters of application of electricfields for transporting the molecules are selected to not have apro-arrhythmic effect on the excitable tissue. In an exemplaryembodiment of the invention the molecule transported is one which causesbreakdown of clots or other occlusions, one which causes angiogenesisand/or one which prevents stenosis or re-stenosis of the vessel.Alternatively or additionally to using a transport pulse, the therapymay be effected using a non-transport pulse, for example a vessel spasmrelaxation pulse. It is noted that pacemaker lead placement usuallyavoids placing the lead over a coronary vessel, in order to providebetter electrical contact with the excitable tissue.

[0018] An aspect of some exemplary embodiments of the invention relatesto using a non-excitatory pulse generating device to both transport amolecule and detect and/or measure an effect of the molecule, forexample an effect on conduction velocity, contractility or actionpotential propagation. Alternatively or additionally to measuring theeffect the device can be used to counteract or block pro-arrhythmiceffects of the molecule and/or of the pulse used to transport themolecule. Alternatively or additionally, the device is used to controlthe type, timing and/or dosage of molecule to be applied.

[0019] An aspect of some exemplary embodiments of the invention relatesto providing one or more types of molecules at a plurality of locationson the excitatory tissue. In an exemplary embodiment of the invention,the amount of molecule transported and the type of molecule transportedat each point is individually controllable. Alternatively oradditionally, the application regimen of the molecule may be predetermined. Alternatively, the application regimen may be varied, forexample in response to needs of the excitatory tissue or in response tothe effect of a previous application. Optionally, a non-excitatory pulseis used to transport the molecule.

[0020] An aspect of some exemplary embodiments of the invention relatesto synchronizing the transport of a molecule with activity of theexcitable tissue, for example the cardiac cycle or cardiac outputvariations caused by activity, to achieve desirable effects, for exampletransport effects. Alternatively or additionally, for example fornon-cardiac excitable tissue, the synchronization is with on-off (orhigh-low) activation cycles of the tissue. Three types ofsynchronization may be distinguished. First is synchronization with theactivity of a single cell (or a region) from depolarization todepolarization. The synchronization may be with any part of theelectrical cycle, including, for example, an onset of depolarization ora plateau. Second is synchronization with the activity of the excitatorytissue within a cycle. Third is synchronization with longer termactivities, such as increase in heart rate due to exercise, uterinecontractions due to impeding labor or digestive activity of the GItract. It is noted that the non-excitatory device can also control theabove excitable tissue activities, alternatively or additionally tosynchronizing with them. In one example, the molecule is transported ata time when it will have the greatest effect on the heart. In anotherexample, the molecule is transported when travel through the uterinetissue is easiest, for example when the muscles of the uterus arerelaxed. Possibly, the non-excitatory pulse is used to extend therefractory time of all or part of the tissue to allow the molecule totravel further in one cycle.

[0021] An aspect of some embodiments of the invention relates toreleasing a molecule from a circulating reservoir, using a field appliedby an electrode associated with a particular blood vessel. Optionally,the particular blood vessel feeds a particular organ or part of an organto be treated. In an exemplary embodiment of the invention, theelectrode is mounted on a stent-like device, on the inside of the bloodvessel. Alternatively, the device is mounted outside the blood vessel,for example being a wire implanted electrode. In an exemplary embodimentof the invention, the circulating reservoir comprises a liposome of atype that releases its contents when a sufficiently strong electricfield is applied to it. Optionally, the stent also includes a reservoirof a same or different molecule. Alternatively or additionally, theelectrode (or a different electrode) also applies a transport field, forexample to release a drug from the reservoir or to transport a moleculefrom the blood flow to the surrounding tissue.

[0022] There is thus provided in accordance with an exemplary embodimentof the invention, electrical treatment apparatus for use with anassociated molecule source, comprising:

[0023] at least one electrode;

[0024] a power source for electrifying said at least one electrode; and

[0025] a controller, which is programmed to activate the power source toselectively electrify said at least one electrode to apply at least oneelectric field including a transport effect for transporting a moleculein a desired manner and a non-excitatory control effect for controllingthe activity of at least a part of a non-cardiac excitable tissue, saidprogramming selected to achieve a desired provision of said moleculeinto said at least a part of an excitable tissue or associatedvasculature, said desired provision being at least assisted by aninteraction between the transport effect and the control effect.Optionally, said controller is hardware programmable. Alternatively,said controller is software programmable.

[0026] In an exemplary embodiment of the invention, said apparatuscomprises a wireless programming input. Alternatively or additionally,said programming comprises programming adapted for said patient.Alternatively or additionally, said programming comprises a setting ofat least one operational parameter of said apparatus. Alternatively oradditionally, said programming comprises a selection or at least oneoperational protocol from a set of available protocols in saidapparatus. Alternatively or additionally, said controller is operable ina testing mode, in which mode a test treatment of a molecule is providedto the patient and the response of the patient to the test is monitoredby said controller. Alternatively or additionally, said apparatuscomprises a synchronization connection to a molecule source containingsaid at least one type of molecule. Optionally, said synchronizationconnection comprises an informative connection that provides at leastone informative signal to said controller, informing of a state ofmolecule release. Alternatively or additionally, said synchronizationconnection comprises a control connection that provides at least onecontrol signal from said controller, to control a state of moleculerelease. Optionally, said molecule source is an electric-field mediatedmolecule source and wherein said control signal generates an electricfield that releases said molecule from said source. Optionally, saidsynchronization connection is comprised in said at least one electrodeused for applying a transport effect. Optionally, said molecule sourceis integral with said electrode. Alternatively, said molecule sourcecomprises blood dispersed molecules.

[0027] In an exemplary embodiment of the invention, said molecule sourceis integral with said at least one electrode used for applying atransport effect.

[0028] In an exemplary embodiment of the invention, said molecule sourceis integral with said apparatus.

[0029] In an exemplary embodiment of the invention, said molecule sourceis external to said apparatus.

[0030] In an exemplary embodiment of the invention, said molecule sourcecomprises a catheter, coupled to said apparatus outside said patient.

[0031] In an exemplary embodiment of the invention, said molecule sourcecomprises a source of a plurality of molecule types. Optionally, saidcontroller controls said molecule source to selectively release at leasta particular one of said plurality of molecule types.

[0032] In an exemplary embodiment of the invention, said apparatuscomprises at least one sensor that senses a functional tissue parameterand provides said sensed parameter to said controller. Optionally, saidsensor measures a functional tissue parameter relating to the entireexcitable tissue. Alternatively or additionally, said sensor measures afunctional tissue parameter relating to a portion of the excitabletissue. Alternatively or additionally, said controller analyses saidsensed parameter to detect an effect of said molecule on said excitabletissue. Alternatively or additionally, said controller analyses saidsensed parameter to detect an activity of the excitable tissue andwherein said controller synchronizes said provision to said sensedactivity. Alternatively or additionally, said controller analyses saidsensed parameter to detect an effect of said transport field on saidexcitable tissue. Alternatively or additionally, said controllermodifies said at least one electric field to modify said transporteffect responsive to said sensed parameter. Alternatively oradditionally, said controller modifies said at least one electric fieldto modify said control effect responsive to said sensed parameter.Alternatively or additionally, said apparatus comprises a watchdog thatdetects an abnormal effect of said applied fields. Alternatively oradditionally, said apparatus comprises a watchdog that detects anabnormal effect of said molecule.

[0033] In an exemplary embodiment of the invention, said apparatuscomprises a user input for receiving an indication of an effect of saidapparatus from said patient. Alternatively or additionally, a singleelectric field applies both of said transport effect and said controleffect. Alternatively, said at least one electric field comprises atleast one transport field and at least one control field.

[0034] In an exemplary embodiment of the invention, said transporteffect and said control effect are provided simultaneously.Alternatively, said transport effect and said control effect are appliedsequentially. Alternatively or additionally, said control effect isselectively applied in association with only some of said transporteffects.

[0035] In an exemplary embodiment of the invention, said apparatuscomprises at least one pacing electrode that is controlled by saidcontroller to apply a pacing pulse. Optionally, said at least one pacingelectrode is comprised in said at least one electrode.

[0036] In an exemplary embodiment of the invention, said transporteffect is provided by an excitatory field.

[0037] In an exemplary embodiment of the invention, said transporteffect is provided by a non-excitatory field. Alternatively oradditionally, an output port for generating an output to said patient.Alternatively or additionally, said control effect is selected toprevent an adverse effect of said transport pulse. Alternatively oradditionally, said control effect is selected to prevent an adverseeffect of said molecule. Alternatively or additionally, said molecule isselected to counteract an adverse effect of said control effect.Alternatively or additionally, said control effect is selected tocounteract an adverse effect of said molecule. Alternatively oradditionally, said control effect is selected to prepare said tissue forsaid transport. Alternatively or additionally, said control effect isselected to extend a period of time suitable for provision of saidmolecule. Alternatively or additionally, said control effect and saidmolecule are selected to cooperate and effect a desired treatment ofsaid tissue. Alternatively or additionally, said at least one electrodecomprises at least one transport electrode for applying a transporteffect of said at least one field and at least one control electrode forapplying said control effect of said at least one field.

[0038] In an exemplary embodiment of the invention, said transporteffect and said control effect of said at least one electric field areapplied using at least one common electrode of said at least oneelectrode. Alternatively, said at least one control electrode isspatially displaced from said at least one transport electrode.

[0039] In an exemplary embodiment of the invention, said at least oneelectrode comprises a point electrode. Alternatively or additionally,said at least one electrode comprises a spiral electrode. Alternativelyor additionally, said at least one electrode comprises a linearelectrode. Alternatively or additionally, said at least one electrodecomprises a mesh electrode.

[0040] In an exemplary embodiment of the invention, said at least oneelectrode comprises a plate electrode.

[0041] Optionally, said electrode comprises a plurality of independentlyelectrifiable contacts. Optionally, said controllers selectivelyelectrifies said independent contacts to achieve a desired, non-uniform,volumetric dispersion of said molecule, relative to said electrode.

[0042] In an exemplary embodiment of the invention, said at least oneelectrode is connected by wire to said controller.

[0043] In an exemplary embodiment of the invention, said at least oneelectrode is a wireless electrode. Alternatively or additionally, atleast one electrode is implantable.

[0044] In an exemplary embodiment of the invention, said at least oneelectrode is mounted on a catheter.

[0045] In an exemplary embodiment of the invention, said at least oneelectrode is an external electrode.

[0046] In an exemplary embodiment of the invention, said apparatus isimplantable.

[0047] In an exemplary embodiment of the invention, said apparatus iscomprises in a cylindrical body adapted for implantation inside a bloodvessel.

[0048] In an exemplary embodiment of the invention, said apparatus iswholly external to the patient. Alternatively or additionally, saidtransport effect comprises iontophoresis. Alternatively or additionally,said transport effect comprises electroporation.

[0049] Optionally, said non-cardiac excitable tissue comprises uterinetissue. Alternatively, said non-cardiac excitable tissue comprisesbladder tissue. Alternatively, said non-cardiac excitable tissuecomprises digestive tissue. Alternatively, said transport effectcomprises releasing a molecule from a circulating reservoir. Optionally,said circulating reservoir comprises liposomes in a blood stream.

[0050] In an exemplary embodiment of the invention, said controllercoordinates the interaction of a systemic molecule and locally availablemolecule, to have a synergistic effect. Optionally, said local moleculeblocks an effect of said systemic molecule. Alternatively oradditionally, said local molecule enhances an effect of said systemicmolecule. Alternatively or additionally, said systemic molecule blocksan effect of said local molecule away from said a locality where saidlocal molecule is provided. Alternatively or additionally, said systemicmolecule enhances an effect of said local molecule.

[0051] There is also provided in accordance with an exemplary embodimentof the invention, electrical treatment apparatus for use with anassociated molecule source, comprising:

[0052] at least one electrode;

[0053] a sensor for sensing a functional state of a non-cardiac tissue;

[0054] a power source for electrifying said at least one electrode; and

[0055] a controller, which is programmed to activate the power source toselectively electrify said at least one electrode to apply at least oneelectric field including a transport effect for transporting a moleculein a desired manner, synchronized to said sensed functional state.

BRIEF DESCRIPTION OF THE DRAWINGS

[0056]FIG. 1 is a schematic illustration of an excitable tissueconnected to a non-excitatory signal providing device, in accordancewith an exemplary embodiment of the invention;

[0057]FIG. 2 is a schematic box diagram of internal sub-components ofthe device of FIG. 1, in accordance with an exemplary embodiment of theinvention;

[0058] FIGS. 3A-3E illustrate various practices of electrodeconfiguration and placement, in accordance with exemplary embodiments ofthe invention;

[0059]FIG. 4 is a schematic illustration of a molecule provisionapparatus, in accordance with an exemplary embodiment of the invention;

[0060]FIG. 5 is a schematic showing of a catheter-based moleculeprovision configuration, in accordance with an exemplary embodiment ofthe invention; and

[0061]FIG. 6 illustrates a vascular treatment device, in accordance withan exemplary embodiment of the invention.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS GENERAL DESCRIPTION OFEXEMPLARY DEVICE

[0062]FIG. 1 is a schematic illustration of an excitable tissue (e.g., aheart) 102 connected to a non-excitatory signal providing device 100 andshowing various optional features of such a connection, in accordancewith an exemplary embodiment of the invention. Although much of thefollowing description focuses on the heart, the method sand devices canalso be applied to non-cardiac excitable tissues, such as the uterus,the GI tract (e.g. stomach, large and small intestines) or the bladder.Where specific cardiac structures are described, such as coronaryvessels and the SA node, corresponding structures in the excitablestructures may replace them. Some structures may have an inexactcorrespondence, for example, a pacemaker location in the uterus or otherexcitable tissue may move. Alternatively or additionally, there may beno corresponding structure, for example, no AV node in the bladder ormultiple corresponding structures, such as the conduction points betweensections of the GI tract. In some tissues, a stimulator, rather than apacemaker, is used.

[0063] In an exemplary embodiment of the invention, device 100 isoperative to provide non-excitatory signals to the heart and/orotherwise control the heart, as a whole or in portions thereof. In anexemplary embodiment of the invention, some or all of the non-excitatorysignals generated by device 100 are used to transport a molecule intothe heart tissue or surrounding tissues, in which tissues application ofan electrical field might adversely affect the heart. One or moreelectrode leads 104 provide electricity from device 100 to one or moreelectrodes 106. A pacer signal electrode 110 may be used to pace theheart, possibly every beat, but optionally not at the same beats as theapplication of non-excitatory signals. A sensor 108 may be used toprovide feedback to device 100 on the effect of the signal and/or thetransported molecule.

[0064] The ability to use a non-excitatory signal rather than a standardpacing signal (a signal whose task is-to generate a dependableinitiation of a cardiac cycle) results in a much wider range of relevantmolecules (e.g. heavy, large or less polarized molecules) and treatmentpossibilities. In particular embodiments of the invention, higherenergies and/or longer transport pulses are used. The following tablecompares a typical pacemaker and a non-excitatory signal providingdevice in accordance with exemplary embodiments of the invention:Characteristic Pacemaker Non-excitatory device Field basis VoltageCurrent or voltage Amplitude 0.5-5 Volts, 2 mA 0.01-40 V, 0.01-150 mADuration 0.05-2 ms 1-1000 ms Effective impedance 500-1500 ohm 240-700ohm, depends on electrode features. Polarity Usually mono-phasicArbitrary Waveform Usually decaying square Arbitrary pulse Electrodetype mono- or bi- polar point Arbitrary electrodes Electrode LocationLimited Arbitrary

[0065] As a result of the freedom in choosing the field basis, varioustypes of transport effects can be achieved, for example voltage basedeffects, current density based effects and/or charge based effects.

[0066] The available current and voltage amplitudes make it easier totransport large molecules, provide deep tissue iontophoresis or evenelectroporation. The available durations complement the availableamplitudes levels by allowing a much longer transport time. The use oflarge electrodes and mesh electrodes, for example as described below,allows the local treatment of many locations in the heart and/or thetreatment or large areas of the heart, which is not possible using astandard pacing lead. Also, this can lower the impedance of theelectrode.

[0067] Various suitable structures and electrical fields are describedin a series of PCT applications filed by Impulse Dynamics (previouslyNTC), now U.S. patent application Ser. Nos. 09/254,900, 09/254,902,09/254,993 and 09/254,994, the disclosures of which are incorporatedherein by reference.

[0068] Exemplary Pulse Properties

[0069] It is suggested in U.S. Pat. No. 5,865,787, an exemplary rangefor iontophoresis is between 200 Hz and 10 MHz, for example between 2and 15 kHz. However, in some embodiments, DC waveforms are used. Wavefrom generators are described in U.S. patent application Ser. Nos.08/110,109 and 07/957,209, both abandoned, the disclosures of which areincorporated herein by reference. With regard to electroporation,frequencies between 0.017 and 10 Hz are suggested. Voltages between 100and 10,000 volts are suggested, with electrodes between 0.5 and 10 cmapart. Pulse durations are suggested between 1 microsecond and 1 second,more typically 100 msec. It is noted, however, that by providing anon-excitatory field to counteract adverse affects, a wider range offields and field parameters is available, so the above should be takenas only exemplary field parameters.

[0070] Additionally, exemplary pulses and/or apparatus which may beuseful can be found in U.S. patent application Ser. No. 08/129,252, nowabandoned, U.S. Pat. Nos. 5,634,899, 5,286,254, 5,087,243, 5,458,568,5,282,785 and U.S. Pat. No. 5,236,413, the disclosures of which areincorporated herein by reference.

[0071] In general, the applied transport pulses may have a net zerocharge flow or they may have a non-zero net charge flow, which may needto be compensated by an after-transport charge zeroing current, thatbalances out the charge emitted by the electrode.

[0072] In some embodiments of the invention, the non-excitatory field iscombined with an excitatory, portion, for example for pacing.

[0073] Exemplary Molecules

[0074] As will be appreciated from the more detailed description below,a wide variety of molecules may be used for practicing variousembodiments of the present invention For convenience, the followingclassification of types of relevant molecules is provided, but it is notto be construed as limiting the range of applicable materials. Manymolecules are known to be provided and/or transported using an electricfiled, for example in the field of patch iontophoresis. It should benoted that a single molecule can belong to several of theclassifications described below. Also, the type of transport method usedmay affect the behavior of the molecule and, hence, its classification.

[0075] (a) Duration of Effect.

[0076] Some molecules have an extended effect, possibly even a permanenteffect. In some cases, the duration is long enough that the heart adapts(“modeling”), whereby a desired effect of the molecule can be achieved.Other molecules have a transient effect, possibly as short as a singleor a small number of beats. Exemplary molecules include Esmolol with aduration of 10 minutes and Adenosine with a duration of tens of seconds.These molecules also have a rapid response.

[0077] (b) Rapidity of Response.

[0078] A differentiation should be made between effect on the heart as awhole and effect on individual cells. Some molecules have an immediateeffect on the heart, for example within a single or a few cardiaccycles, for example Adenosine in seconds, and Esmolol in minutes.Others, for example genes for providing ionic channels and/or forchanging conduction velocity, may have their main effect only after aconsiderable period of time.

[0079] (c) Size of Molecules.

[0080] Molecules come in all size ranges. One important effect of themolecule size is its ease of entry into a living cell. Another is theease of transport by electrophoresis. An example of a small molecule isnitroglycerin. An example of a large molecule is a DNA anti-sensemolecule.

[0081] (d) Polarization.

[0082] The degree of polarization of a molecule affects not only itssolubility and ability to enter cells but also the type of electricfield which can most efficiently transport it. Using stronger fields,various pulse envelopes, various frequencies and/or longer pulsedurations supports the transport of molecules that are otherwisedifficult to transport.

[0083] (e) Existence of Hydrophobic and Hydrophilic Moieties.

[0084] Such moieties affect the behavior of a molecule during transportand during entry into a cell.

[0085] (f) Ability to Self Transport into Cells.

[0086] Some molecules, such as viruses and liposomes can more readilyinsert themselves into cells than raw DNA.

[0087] (g) Type of Adverse Effect on Cell.

[0088] Some molecules adversely affect some types of cardiac cells, forexample killing or disabling them. Other molecules only affect somefunctions of the cell, for example their electrical activity, withoutaffecting other functions, such as their basic metabolism or lifeexpectancy. In a particular example, ion channels provided directly orgenes for ion channels provided) can modulate electrical activity and/orcause metabolic changes. This can result in death for some cells and ina cure for other cells. Specifically, increased population of membranepotassium channels can shorten action potential, lower membranepotential and/or change the refractory periods of a cell.

[0089] (h) Drug Combinations.

[0090] Instead of transporting only a single molecule, multiplemolecules may be transported, possibly through different means. If theeffect of the two molecules together is different from that of theindividual molecules, in type and/or amplitude, better targeting ofportions of the heart can be achieved, for example by providing the twomolecules so they only intersect in one area of the heart.

[0091] (i) Drug vs. Non-Drugs.

[0092] Although many of the suitable molecules are drugs, othermolecules may also find use, for example signaling molecules, such ashormones, cytokines and/or paracrinic signals/hormones, both natural andsynthetic. Additionally or alternatively, various types ofgenetic-related molecules may be used. Alternatively or additionally,membrane proteins, such as voltage gated channels may be used.Alternatively or additionally, structural proteins, such as actin, maybe used. Alternatively or additionally, housekeeping proteins, such asUbiquitin, may be used. Alternatively or additionally, solutes, such asglucose, cAMP, AMP, ADP, ATP and metal salts may be used.

[0093] (j) Protection of Molecules.

[0094] Although drugs and other molecules may be transported in a rawstate, in some cases, the drugs may be protected against interactionwith the, blood, extra-cellular liquids, cell membranes and/or othermaterials which intervene between the drug source and its target. Suchprotection may take the form of encapsulation, for example in liposomesor incorporation, for example by caging into polyester gels.

[0095] k) Association for Transport.

[0096] In some cases, the molecules may be associated with othermaterials, to assist in transport or in the entry into cells and/ornucleus of cells. In one example, a drug may be adsorbed to a pellet,which pellet is more easily transported by the fields. In anotherexample, the molecule is incorporated in a virus.

[0097] (l) Genetic Material.

[0098] As will be described below, a particular desirable class ofmolecules is gene-related molecules, such as DNA, RNA, mRNA, etc.,anti-sense molecules and proteins that affect transcription.

[0099] (m) Microorganisms.

[0100] In some cases, it may be desirable to insert complete orsemi-complete microorganisms or cell components into living cells, forexample mitochondria, viruses or plasmids.

[0101] As can be appreciated, the molecule may interact in a beneficial,neutral or adverse manner with one or more of the transport method, theprovision method, the cardiac sensitivity (e.g., to electrical fieldsand certain molecules) and/or the instantaneous activity of the heart.These effects (if negative) may be overcome or enhanced, in someembodiments of the invention, by suitable varying of the transportmethod and of the molecule properties, for example as classified above.

[0102] Gene Therapy

[0103] In an exemplary embodiment of the invention, electroporationtechniques are used to provide gene therapy to the heart. In genetherapy, genetic material or a carrier thereof, such as plasmids,artificial chromosomes or viruses particles are provided into a cell.Examples of suitable genetic material include, anti-sense DNA, RNA andpoly-peptides to block the expression of genes which have an undesirableeffect. In another example, tagging material is inserted to the cell, toserve as a trigger for more complex activity. In one example,regeneration of particular cells is achieved by tagging cells using agenetic marker. A second therapy is applied systemically but is onlytaken up or only triggers the tagged cells. The provided geneticmaterial may be used for various purposes, including, for examplemodifying the cell genotype, curing a genetic defect or a viral disease,causing a cell to differentiate in a desired manner or changing thefunction of a cell, such as changing the conduction velocity, actionpotential profile and/or leakage current characteristics of the cell.

[0104] In a paper in Nature 1999, September 23; 401 (6751) pp390-394,the disclosure of which is incorporated herein by reference, Mulligan RC, et al. describe a mechanism for targeting stem cells to where theyare required in the body. It is believed such stem cells are targeted bya localized inflammation process, which process may be artificially andlocally induced using a suitable molecule in accordance with anexemplary embodiment of the invention.

[0105] A particular aspect of some types of genetic therapy (and also ofsome drugs) is that the cell's behavior is modified. As a result, thecell may affect other, neighboring, cells, for example by creatingcopies of the genetic material (e.g., virus) or by extruding hormonesand other cellular-communication chemicals.

[0106] In another example, tissues near clogged arteries are geneticallymodified, for example with a plasmid, to generate an anti-coagulant, aclot dissolver or a vascular dilator. These materials are optionallyprovided locally in a therapeutic concentration, so that they arediluted in the general blood stream. Alternatively or additionally,these materials only reach active concentrations and/or requiredactivity times if the blood volume flow is reduced relative to normalblood vessels.

[0107] In another example, the heart as a whole is affected by thetreatment of a small set of cells. For example, cells can be treated toinclude more calcium or sodium channels, thereby causing the treatedcells to form a pacing loci. Depending on the type of treatment (e.g.,plasmids, viruses or channel proteins), the effect may vary in duration,thereby allowing different pacing locations to be chosen.

[0108] Device Components

[0109] Apparatus suitable for performing (or being modified to perform)the function of device 100 of generating non-excitatory signals aredescribed, for example in PCT application PCT/IL97/00012, and PCTpublications WO 99/03533 and WO00/53257, the disclosure of which isincorporated herein by reference.

[0110]FIG. 2 is a box diagram of exemplary sub-components of anexemplary device 100, in accordance with an exemplary embodiment of theinvention. Although many possible sub-components are shown, someembodiments do not require all of the sub components, for example, someembodiments do not include watchdogs or programming input. For clarity,connecting lines between the sub-components are not shown.

[0111] The non-excitatory signals are generated by a signal generator132 and outputted to the electrodes via an output coupler 140. The powerfor driving the output signals maybe provided directly from a powersources 120, or, more typically, using a capacitor bank 126 toaccumulate power. In a device that includes a pacing feature, some orall of these elements may be optionally shared between the pacemaker andthe non-excitatory signal pathways.

[0112] A CPU 122 is optionally provided to control device 100. A clocksource 128 may be used to maintain an internal clock.

[0113] In an exemplary embodiment of the invention, CPU 122 uses astate-machine model of the heart to assess if the heart is operating asexpected and/or to determine the possible timing of non-excitatorypulses, especially for drug transport. Alternatively or additionally,other state-machine models may be used. Alternatively, a non-statemachine model is used. Various types of models are described in “Designof Cardiac Pacemakers,”, ed. John G. Webster, 1995, by the Institute ofElectrical and Electronics Engineers, Inc., New York, N.Y., thedisclosure of which is incorporated herein by reference.

[0114] In an exemplary embodiment of the invention, CPU 122 utilizessensor data from a sensor input 130, in determine applicationparameters. Although only a single sensor is shown, in some devices,more than one sensor is used. Optionally, device 100 includes a memory134 for storing programming instructions, applied sequences and/orstatistics and/or full data of the response of the heart at varioustimes.

[0115] In an exemplary embodiment of the invention, a programming input136, preferably wireless, but optionally wired, is provided to allowprogramming the device, for example using RF, ultrasound or magnets.Alternatively or additionally, a feedback output 138 is provided forpresenting information from device 100 to an external programmer oruser. A particular use of the programming features is to assist insetting and modifying treatment regimes and/or adjusting existingregimes to take into account observations by a treating physician.Another use is allowing a patient to be treated at home and report byremote means, such as a telephone, the actual treatment and/or itseffect. The setting of treatment parameters may also be by remote means.Another possible use of output 138 (and programming input 136) is forreceiving feedback from the patient.

[0116] In an exemplary embodiment of the invention, the user of thedevice can activate device 100, using a handheld remote controller,which may optionally also beam energy, for example using RF radiation.Alternatively or additionally, the remote control may include activationlogic for the device. A single remote controller can activate multipledevices, for example one or more of, a non-excitatory signal controller,a pacemaker, a drug targeting electric field(e.g., device 100) and adrug reservoir, to achieve a desired treatment effect. In an exemplaryembodiment of the invention, the user activates device 100 in responseto pain, for example, to release blood vessel dilating molecules inresponse to angina pectoris or to inhibit premature uterinecontractions.

[0117] In an exemplary embodiment of the invention, device 100 includesone or more watchdogs 124. Two types of watchdogs may be utilized in anexemplary embodiment of the invention. A first type of watchdog watchesover the device itself, to assure that it is working within theoperational parameters defined for it. For example, two processors runconcurrently, and if one is not responding, the other one generates analert. A second type of watchdog watches over the heart, to assure thatthe heart does not, as a result of the treatment, exceed operationaland/or functional parameters defined for the heart's activity. In oneexample, the watchdog checks to see if the heart is acting differentlyafter the transport pulse. Alternatively or additionally, the watchdogsearches for particular tattletale signals of damage more likely to becaused by the treatment, for example, a certain type of arrhythmia in anpro-arrhythmic drug treatment or VT caused by the transport pulse. Thedamage and/or danger may be immediate, for example the detection of aninjury current or of VT. Alternatively or additionally, the damage ordanger detected may be longer term, for example, if the treatment causesa forced relaxation of part of the heart, which relaxation may causehypertrophy or an aneurysm. A separate feedback loop may be provided todetect if the treatment is having a desired effect, for example adesired remodeling of cardiac tissue. Optionally, the watchdog isimplemented as a separate processor and/or sensor. Alternatively, thewatchdog comprises separate software.

[0118] The output of the watchdogs may include, for example, output tothe patient, to a remote service center and/or may include a changing inthe device parameters, for example to stop or modify the treatment or toprovide symptom countering treatment, such as blocking of undesirableaction potentials of transport of a different molecule.

[0119] In an exemplary embodiment of the invention, device 100 isimplantable. Thus, device 100 is optionally encased in a small capsule,to be implanted in the chest or the stomach of the patient. Device 100may be integrated with a pacemaker or it may be a separate entity.

[0120] Alternatively, device 100 is external. The electrodes areoptionally internal, optionally reaching the heart either via a catheterinserted in the blood stream or via a hole in the skin, for example toeffect a near-by vessel or part of the heart. The molecules may beprovided using the same catheter or in a tube alongside the electrodes.Alternatively, other molecule provision methods, for example asdescribed below, may be used.

[0121] Alternatively, the electrodes may be external to the body, forexample as used in some external pacemakers. Various electrode schemesmay be used, including, two large, two small, one large and many small,an array, electrode(s) in lungs and/or electrode(s) in esophagus.Optionally, the electrification of the electrodes matches the heart'sposition and/or global or local refractory state.

[0122] In an exemplary embodiment of the invention, an external deviceis used for a short-term treatment, such as for gene therapy, forrecovery from surgery or for recovery from a serious arrhythmia or acuteischemic event. Alternatively, an implanted device may be used formedium term treatment. Alternatively, a previously implanted device maybe reprogrammed to apply a non-excitatory pulse as described herein. Insome embodiments of the invention, only the electrodes are implanted andwireless. The rest of the device is external and is used to power anddrive the electrodes, for example using RF radiation.

[0123] Alternatively or additionally, the functionality described hereinmay be integrated with a different device, for example, a stent. In oneexemplary application, a stent applies non-excitatory pulses totransport an anti-re-occlusion drug into the blood vessel walls. Thedrug may be provided in many ways, including, for example, from theblood stream, from a reservoir of the stent or from a catheter.

[0124] In an exemplary embodiment of the invention, the device is adedicated device. Alternatively, however, some or all of thefunctionality may be achieved using a modified pacemaker, in whichsubstantially only the programming and/or electrodes are modified. Thesuitability of existing pacemaker circuitry and/or power supplies maydepend, for example, on the effect desired (e.g., electroporation oriontophoresis) and on the molecule size, polarity and/or otherproperties, such as protective enclosure.

[0125] In one embodiment of the invention, device 100 comprises a kit oftwo devices, one for providing the electrical fields and one forproviding the molecule. Either or both of the devices may beimplantable, external partially implanted or transvascular. A drugsource controller 142 is optionally provided in device 100 to controlthe provision of molecules. Alternatively, a third device, such as anexternal or implanted controller (not shown), synchronizes the operationof the two devices.

[0126] Alternatively, one device is used for transporting the moleculeand another device is used for pacing or non-excitatory control(molecule provision can be by either of the devices or using a separatedevice). In this embodiment, the other device can be used to counteractadverse effects of the transport and/or the applied molecules. In anexemplary embodiment of the invention, the two devices can communicate,for example using a wireless link, such as an ultrasonic link or a wiredlink, such as a fiber optic cable.

[0127] Electrodes

[0128] FIGS. 3A-3E illustrate various practices of electrodeconfiguration and placement, in accordance with exemplary embodiments ofthe invention. The type of electrode can be an important factor indetermining the strength and distribution of the electric field. Bychanging the type and shape of the electrode, different types oftransport maybe effected. In addition, the depth of penetration andspatial distribution of the molecule into the cardiac tissue isaffected, not only by the electrification of the electrode but also bythe shape of the electrode. The placement of the electrodes determineswhich part of the heart is affected and, together with a suitableselection of electrode type and shape, allows localized treatment ofspecific portions of the heart, such as the SA node. In addition,certain multi-electrode types, such as mesh electrodes or electrodearrays, provide a greater temporal and spatial control of the electricfield

[0129] Although the electrodes may be placed anywhere on the heart(e.g., inside the muscle, inside blood vessels or inside the heart), insome embodiments of the invention, the electrodes are placed at anarterial entrance, an area of infraction, at an ectopy site, near ablock or an AV node, inside or at a border of a scar and/or at thenervous plexus.

[0130]FIG. 3A illustrates the placement of a point electrode 160 on acardiac segment 150. In a point electrode the strongest part of theelectric field is in a close proximity to the electrode, indicated by adotted line 162. If a bi-polar electrode is used, the localization ofthe field is even greater, being mainly between the two electrodes.Alternatively, a common return electrode may be used, for example acasing of device 100 or a second electrode attached to a substantiallyremote portion of the heart. Various tip shapes may be provided, forexample, solid or meshwork balls, multi-fingered tips, spirals and/or abarb.

[0131]FIG. 3B illustrates the placement of a line electrode 164 oncardiac segment 150. A simplest type of line electrode has contactsalong its length, as shown. Alternatively, a line electrode may comprisea plurality of spaced apart point electrodes which may be electrified inparallel or possibly in various orders, as a linear array. A region 166affected by electrode 166 is substantially larger than that of a pointelectrode. This can be used to apply a molecule to a larger portion ofthe heart or even to create a “fence” by applying a desensitizing drugalong the electrode. In some embodiments of the invention, such a lineelectrode is curved.

[0132]FIG. 3C illustrates the deployment of a pair of line electrodes168 and 170. The affected area (in which there is a significant electricfield) is marked by a dotted line as 172. The two electrodes may beelectrified with a same polarity or with opposing polarities.Additionally, if one or both lines comprises a linear array of pointelectrodes, these point electrodes may be scanned in synchrony or not.The size and shape of affected area 172 is dependent on the type ofelectrification. For example, if the two electrodes are electrified withdifferent voltages, there will typically be very small field outside ofthe electrodes, which may, in some embodiments, prevent the moleculesfrom being transported outside of the electrified area.

[0133]FIG. 3D illustrates a mesh electrode 174 having a plurality ofvertexes 176. In one embodiment, the entire mesh is electrified as asingle element. In another embodiment, only the vertexes (or othersegregated section of the mesh) are electrified (e.g., an array). Inanother embodiment, at least some of the vertexes can be selectivelyelectrified. One advantage of selectively electrifying mesh (or line)vertexes in an electrode array is that there is finer control over theshape, location and intensity of the field and this control can beexerted in real-time, without requiring movement of the electrodes. Oneuse of such control is for modifying the transport field to effect acertain transport effect, for example as defined below, for adapting apre-conceived electrification protocol to a particular heart and/orsituation and/or to match the actual or expected propagation of themolecule in the heart. Alternatively or additionally, such control maybe used to match the propagation of electrical waves in the heart or tomatch changes in the contractile state of cardiac muscle. In oneembodiment, these states are estimated using a model. Alternatively,these states may be measured using suitable sensors.

[0134] In a particular embodiment of the invention, the molecule isprovided at a mesh electrode. Optionally, the mesh electrode iselectrified in a manner which distributes the molecules in a desiredmanner, for example electrifying pairs of vertexes in the mesh such thateach such pair defines a different transport vector, for example all theelectrification pairs sharing a common electrode. Alternatively oradditionally, the timing, amplitude and/or other electrificationparameters are different for each electrode pair, taking into account,for example the different average activation times of the heart and/orthe instantaneous different activation time. Such an instantaneousactivation time may be detected, for example, using the mesh electrodesas sensors or by providing dedicated sensors.

[0135]FIG. 3E illustrates the use of a plate electrode 178. Such a platemay have apertures (not shown) formed in it, so it is not completelysolid. In an exemplary embodiment of the invention, electrode 178 mayserve as a reservoir, for example including a suitable matrixencapsulating the molecule, or having an inner volume, for exampleenclosed by an electrically permeable membrane.

[0136] The electrode configurations of FIGS. 3A-3E may be appliedoutside of the heart muscle, inside the heart muscle or on the inside ofthe heart. Additionally, when using electrode pairs, one may be insidethe heart tissue and one outside the heart tissue. Alternatively oradditionally, at least one of the electrodes may be floating inside theheart. In some embodiments, the electrodes are coated with a layer ofmaterial to retard clotting.

[0137] Molecule Source

[0138] The molecules may be provided in various manners; for example asdescribed below. Two main types of provision should be differentiated,localized provision and systemic provision. In localized provisionmethods, the concentration of the supplied molecule is significant onlyat or about the treatment area. One possible advantage of this type ofprovision is that effects on other body portions are reduced. Anotherpossible advantage is that a smaller amount of molecule may be used.Another possible advantage is that a higher concentration of moleculecan be realized at the treatment zone.

[0139] In systemic provision methods, one possible advantage is thatthere is no need to provide a molecule at precise temporal and/orspatial coordinates. Rather, the electrical transport effect is used tolocally increase the effectiveness of the molecule, by transporting itto the tissue to be affected, for example from the blood stream.

[0140] One method of localized molecule provision is in association withone of the electrodes of the device 100. FIG. 4 is a schematicillustration of a molecule provision apparatus, in accordance with anexemplary embodiment of the invention. A lead 180 has at its end anelectrode 182, for applying a non-excitatory electric field to a heartsegment 150 and a drug-eluting portion 184. In one embodiment, lead 180is a hollow tube which caries the molecule from a reservoir insidedevice 100 (not shown). Such a reservoir is amenable to replenishment,for example as known in the art of replenishing implanted medicationpumps. Alternatively, lead 180 itself may serve as a reservoir. In oneexample, lead 180 is a hollow tube which caries the molecule from areservoir inside device 100 (not shown). Such a reservoir is moreamenable for replenishment, for example as known in the art ofreplenishing implanted medication pumps. Alternatively, lead 180 itselfmay serve as a reservoir. In one example, lead 180 is hollow and filledwith a liquid medicament. In another example, the medicament is solidand is dissolved by body fluids only at the distal end thereof. Inanother example, a molecule is constrained in a gel matrix insertedinside lead 180. In some embodiments, an electric field is used toadvance the molecules along the lead, for example as described in U.S.Pat. No. 5,865,787. In general, a reservoir may be useful where localprovision of a molecule is desirable.

[0141] Alternatively or additionally, tip 184 may be porous, allowingthe molecules to slowly diffuse out.

[0142] In an exemplary embodiment of the invention, an electric fieldapplied by electrode 182 is used to elute the molecule from tip 184. Tip184 maybe, for example, between electrode 182 and the heart, on anopposite side of the heart from the electrode or side by side with it.Additionally, one or both of electrode 182 and tip 184 may be insertedinto the cardiac tissue. A same field may be used for eluting and fortransport or a different field may be used. Alternatively oradditionally, one or more additional electrodes 184 may be used toassist in the eluting. PCT publication WO 98/15317 describes a limitedrange of possibilities for selectively eluting molecules from adrug-eluting tip. In exemplary embodiments of the instant invention, thefreedom of electrode shape, charge polarity, charge amplitude, chargeduration, charge location and waveform allow a much wider range ofmethods to be practiced. As a result, it is possible to selectivelyelute one of several molecules which are stored in one or morereservoirs about tip 184. In one example, the polarity of the fielddetermines the polarity of molecule eluted. In another example, thefield amplitude determines what size molecule is transported and/oropens pores in a barrier material between the molecule reservoir and theoutside of the tip. In another example, molecules with dipole chargesmay be selected by applying a suitable elution frequency. Alternatively,non-electrical transport methods are used to free the molecules, forexample, operating pumps or openings in a reservoir.

[0143]FIG. 5 is a schematic showing of a catheter-based moleculeprovision configuration, in accordance with an exemplary embodiment ofthe invention. A catheter 188 is used to provide the desired moleculefrom outside of the body, to its tip in a vicinity of electrode 192.Alternatively or additionally, the catheter may be drug eluting over aportion of its length. The molecules may be provided at a location fromwhich they are advanced away from the electrode. Alternatively, themolecules may be attracted towards the electrode. Alternatively oradditionally, the electrodes may be electrified to prevent the advanceof the molecules in an undesired direction.

[0144] Alternatively to providing the molecules locally to electrode192, the molecules may be provided into a vascular bed of the areaadjacent electrode 192, for example into a main coronary artery. In anexemplary embodiment of the invention, the application of the electricalfield is timed to match the arrival of the molecule bolus. Alternativelyor additionally, the provision of the molecule is over an extendedperiod.

[0145] In an exemplary embodiment of the invention, the application ofthe electrical field (and/or localized molecule provision) is timed towhen blood flow is slow, to avoid dissipation of the molecule.Alternatively or additionally, tip 190 may block the flow of blood,optionally temporarily, for example using an inflatable balloon collar.Alternatively, a double collar catheter having two spaced apart collarsand a hollow lumen, may be used to block flow to only a portion of avessel, while providing a molecule to the blocked off area and allowingthe flow of blood to by-pass through the lumen of the catheter.Alternatively, tip 190 may be pressed against the tissue to be treated,optionally in the direction of the field, so that the molecule can onlyadvance through the tissue and not into the blood flow. Alternatively oradditionally, a local electric field may be applied to reduce orincrease blood flow, for example by relaxing or contracting the bloodvessel muscles. Such relaxation may also assist in the penetration ofthe molecule through or into the vessel walls.

[0146] The timing of the application of the electric field may take intoaccount a model of propagating of blood in a heart in general and/or inthe parficular treated heart. Such a model may be derived, for example,from radiological studies of the propagation of radio-opaque dyes in thecoronary vessels.

[0147] Alternatively or additionally, tip 190 injects the moleculedirectly into tissue. Such injection may be achieved by providing asharp tip at tip 190 or by the catheter exiting the blood flow or beingprovided not through the vascular system, for example through tissue oralong body lumens such as the lungs or the GI tract.

[0148] Electrode 192 may be implanted by a catheter that may also beprovided from outside the body. In one exemplary embodiment of theinvention, the catheter and electrode are combine in a single invasivedevice. This device may be inserted into the body and brought to adesired treatment location, for example the apex of the heart. Then, amolecule is eluted (optionally at the electrode) and an electric fieldapplied to treat the region. A bipolar electrode may be used or thesecond electrode may be provided outside the body, or inside, forexample using a second catheter, between which catheters a transportelectric field and/or a heart control electric field are applied.Optionally, the tip of the catheter inside the body includes a graspingdevice for attaching to a portion of a tissue adjacent the treatmentarea. Such a catheter optionally includes a sensor for sensing localactivity of the heart or is controlled (e.g., field application and/ormolecule provision) using an external sensor, such as a 12-lead EKGsensor. Possibly, the catheter elutes a molecule along a portion of itslength, allowing, for example, a length of a coronary vessel to betreated. Different molecules or concentrations of molecules may beeluted at different points along the catheter.

[0149] The combined catheter-electrode may be provided via the vascularsystem. Alternatively, an endoscopic or throactoscopic approach may beused. Such a device may be used for relatively chronic treatment, forexample one treatment a week after a coronary event. Alternatively, thedevice may be used for acute treatment, for example to provide a drug toa portion of the heart during cardiac surgery.

[0150] Another method of localized provision of a molecule is byinjecting it into the heart using a syringe (from outside the body).Optionally, the entry and retraction of the syringe are controlled usinga spring-loaded device, so that contact with the heart is during anon-excitable portion of the cardiac cycle, to prevent arrhythmia.

[0151] Many systemic molecule application methods are known and may beused with various embodiments of the invention, including drip-feedinginto a vein, catheterization into the right atrium, ingestion,inhalation and intra-vascular or intra-muscular injection.

[0152] In an exemplary embodiment of the invention, device 100 includesa data input port for indicating when a drug is injected or otherwiseprovided into the user, so that the application of the non-excitatorysignal can be timed to when the drug (or other molecule) is available atthe electrodes. Such an input may be provided for example using a magnetor an RF field.

[0153] Transport and Selectivity

[0154] The non-excitatory pulse used for transporting the molecule maybe a separate pulse from that used for a non-excitatory based treatment,it may be a combined transport-treatment pulse or it may be a same pulsewhich has both a treatment effect and a transport effect. Possibly, amolecule may be selected or adapted for treatment by it matchingavailable pulse forms or pulses which have a known therapeutic effect.

[0155] As described above, the transport mechanism may be that ofremoving the molecule from a reservoir using an electric field.Thereafter, the molecule can diffuse into the adjacent tissue (orwherever the blood caries it) or an active transport (e.g., an electricfield) into adjacent tissue may be used.

[0156] Two types of transport can be differentiated, transport intotissue and transport into cells. Transport into tissue can be, forexample, iontophoresis. Alternatively, uncharged molecules, for examplethose with a dipole charge may be used. Alternatively or additionally,the application of the electric field may make the tissue more porous tothe diffusion of the molecule.

[0157] In one exemplary embodiment, of the invention two or more of theabove transport mechanisms are used together. For example,electroporation into the cardiac cells themselves may be used instead ofor in addition to iontophoresis, for example, iontophoresis to advance adrug into the cardiac tissue and then electroporation to insert the druginto the cells. The two mechanisms may optionally be applied in separatecardiac cycles.

[0158] Various types of selectivity may be achieved, besides selectivityof the transported molecule, described above. In one example, theiontophoresis of a molecule is affected by the tissue through which themolecule travels. In another example, the field strength used forelectroporation is selected to affect only certain types of tissue, forexample based on their taxonomy (muscle vs. nerve cells) or based ontheir health.

[0159] It should be noted that the molecules may be transported duringany part of the cardiac cycle, to take advantage of (or avoid)particular electrochemical and/or physiological conditions.Alternatively or additionally, a molecule may be selectively providedand/or transported so that it is available at the cells when theirchannels in the cell membrane open as part of the cardiac cycle. Such amolecule may be transported through the channel or it may be used toblock the channel or to maintain it open for longer periods.Alternatively or additionally, a transport pulse may be provided tomaintain the channels open for longer periods (or close them), forexample to provide a desirable biochemical state in the cell with whichthe molecule can interact or to allow the molecule to enter through theopen channel. The exact electrification parameters may need to bedetermined for a particular patient, tissue type and/or tissue healthstate.

[0160] It should be appreciated that diffusion of drugs and othermolecules in the heart may be enhanced by diffusion between cardiacmuscle cell groups, in which groups, the cell-ends are fused together.Alternatively or additionally, the transport may be affected by thefiber direction and/or other macro-cellular structures. These effectscan be used to selectively diffuse molecules along a direction. Also,these variation in tissue characteristics may affect a desired electricfield to be used for transport between and/or into cells. In anexemplary application, an electric field is used to transport a moleculeinto endocardial trabecula, while they are being filled. Then when theycontract and force blood into the surrounding cardiac tissue, thetransport is enhanced. Optionally, a second electric field is timed tothe contraction.

[0161] Alternatively or additionally, the transport of molecules maytake into account the variations in muscle tone over the cardiac cycle.Thus, an increased field may be required while the muscle is tense.Alternatively, the transport is selectively applied while the muscle isrelaxed, to increase the depth of penetration of the molecule.Alternatively, the transport is applied when the muscle is tense, toassure a shallower penetration, In an exemplary embodiment of theinvention, a multi-beat transport scheme is used, in which a molecule istransported to an area to be treated by a transport process which islonger than one beat. In one example, a molecule may be transported 1 mmeach heart beat, for a total of five beats, to achieve a penetrationdepth of 5 mm.

[0162] Type of Control

[0163] The control exerted on the heart using the molecules and/or anon-excitatory electric field can be of various types. Three particulartypes of control which may be desirously achieved are global control,local control and global control using local interactions.

[0164] In an example of global control, a gene may be provided to theentire heart, to correct a disease causing mutation in a particularpatient.

[0165] In an example of local control, a drug may be provided to aninfracted area to promote healing or prevent further damage.

[0166] In an example of global control mediated by local interactions,control of the SA node, of the AV node or of a particular conductionpathway may be used to affect the activation of the heart as a whole.

[0167] It should be noted that the fastest action potential conductionin the heart is near the surface of the inside of the ventricles.Controlling the conduction velocity in this area provides an opportunityto affect the activation of large sections of the heart. This area isalso somewhat more accessible to some electrically based transporttechniques, since a drug can be applied directly to the inside of theheart.

[0168] As described above, with reference to molecule provision, thetype of interaction of the molecule with the heart may depend oncellular or on cardiac processes, for example, a drug may be provided tocoincide with the high levels of availability of free calcium.Alternatively, a molecule may be provided so that it is available over alonger period of time, such as an entire beat or several heart beats.Exemplary periods of time for a molecule to be available are 0.1, 1, 10,100 or 1000 seconds, e.g., in some cases substantially permanently. Theduration of the molecule effect, which may be divorced for the durationof availability may be, for example, 1, 10, 100 or 100 seconds, e.g., insome cases substantially permanent. Some types of long cardiac-relatedcycles include the circadian rhythm exercise-rest cycles and theapplication of molecules to the heart to permanently change the shapeand/or activation of the heart. In an exemplary application, electricfields are used to stimulate angiogenesis and a stimulating molecule,such as VEGF is also provided to enhance the angiogenesis effect. Themolecule (and transport field) may be applied every beat or only everyfew beats. In some embodiments of the invention, a single transportevent continues over several beats or has the duration of several beats,for example with the local tissue being desensitized so it does notcontract.

[0169] In an exemplary embodiment of the invention, selective moleculeproviding is used to control the heart locally and/or for temporallyshort periods, such as seconds or tens of seconds. This effect isachieved by selectively transporting fast acting drugs to targettissues, in short times and without substantially providing the drugs tonearby tissues. Alternatively or additionally, this affect is achievedby electrically (or using suitable eluted pharmaceuticals)de-sensitizing neighboring tissue from responding to the drugs.

[0170] Interaction Between Device and Excitable Tissue, Other ThanTransport

[0171] The interaction between device 100 and the molecule may extendbeyond transport. For example, one or more of the following effects canbe achieved instead of or in addition to transport:

[0172] (a) Device 100 applies fields that counteract or avoid negativeeffects of the molecule. As a result, molecules with a higher toxicitymay be used, used at a higher dosage and/or used in a less rigidlymonitored situation. In one example, device 100 applies fencing ortissue desensitizing fields, as described in some of the aboveapplications, to prevent propagation of undesirable activationpotentials in the heart. In another example, device 100 applied fieldswhich reduce conduction velocity in tissue whose conduction velocity isundesirably increased by the provision of a drug. Alternatively, themolecule may serve to prevent or counteract an adverse effect of thenon-excitatory control pulse.

[0173] (b) The molecule may be provided to avoid or counter act negativeeffects of the applied fields. The fields in question may be excitatoryor non-excitatory. In one example, a molecule is provided to prevent orcounteract edge effects at the fringes of applied non-excitatory fields.

[0174] (c) Device 100 applies fields that synergistically interact withthe molecule. In one example, each of the molecule and the field work toincrease cardiac contractility, and the combination is synergetic. Onesuch exemplary molecule is caffeine. Another example of synergisticinteraction is provided by Dobutamine (an example of an adrenergicagonist).

[0175] (d) Device 100 applies fields which prepare a portion of theheart for an applied molecule. Such preparation may include, forexample, relaxation to allow better transport by an electric field, orwithout one. Another example is prevention or provision of blood flow toa portion of the heart, by manipulation the cardiac activation profile,Thus, a transport-related electric field may be applied before anymolecule is provided. Another example of preparation is keeping asegment of the heart from contracting so that it has more availableenergy to respond to a drug. In another example, the electric fields maybe applied to extend the duration of a cardiac cycle, to allow more timefor transport of a molecule between beats or to allow more time for themolecule to take effect. In another example, a blood vessel wall isstimulated or relaxed to assist or otherwise modulate the transportthrough the vessel wall. Such control is especially useful forpreventing the transport of a molecule in an undesired vector. Thetransport related field may be applied near the location of thetransport filed or at a remote location. For example, a field thatdilates or contracts blood vessels may be applied to control the flow ofblood through the area being treated or the molecule provision area. Insome embodiments of the invention, vascular control is providedindependent of transport pulses and/or molecule provision.

[0176] (e) Device 100 applies fields, which by themselves do notinteract with the molecules, but, as part of a complete control scheme,both these fields and the molecule act together to effect a desiredcontrol of the heart. In one example, a drug may be used to reduceoverall conduction velocity in a ventricle, while an electric field isapplied to increase the velocity at a certain location in the ventricle.In another example, a locally provided molecule is used to stimulateangiogenesis, while an electric field is used to reduce the workperformed by the treated tissue, to allow it to receive and/or haveavailable energy for the angiogenesis.

[0177] The size of the area and/or volume to which a non-excitatoryelectric field is applied may coincide with the molecule-affected area.Alternatively, it may be smaller, for example to apply a desired localeffect or larger, for example, to counteract fringe effects.Alternatively, the electric field may be applied to a significantportion of the heart, for example to most of a ventricle, for example toenhance a stroke volume. Possibly, the molecule is used to interact witha defibrillation field. By selectively applying the electric fieldsand/or the molecules, spatial and/or temporal selectivity of the aboveeffects may be achieved.

[0178] In some embodiments of the invention, there may be no interactionbetween the molecule and the other electric fields applied by device100.

[0179] Calibration

[0180] Device 100 may be programmed and/or have parameters selected tomatch a particular patient (described below). Alternatively oradditionally, one or more of a set of programs may be selected to beapplied by device 100.

[0181] In an exemplary embodiment of the invention, prior to activatinga treatment function of device 100, the patient state is evaluated, todetermine a desirable treatment. In some embodiments of the invention,this evaluation is performed using device 100, in a purely sensory mode,or, optionally, with device 100 applying test treatments and determiningtheir effects. Alternatively or additionally, various external stimulimay be provided, for example pharmaceuticals and their effects and/orinteractions with device 100 monitored by device 100 and/or otherapparatus.

[0182] During evaluation, one or more of the following regionalpathologies may be identified: Scar, Hibernation, Ischemic and/or HRdependent ischemia. The identification may use various imaging methods,for example ECHO for hypo/dis/a-kinesis of ventricular walls. Variousmethod may be used to evaluate perfusion, for example Technetium basedimaging. Position sensing based methods may be used to evaluate regionalfunction, for example systems provided by the Biosense Inc. corporationand/or ECG systems. These methods could be used to design and focus thetreatment to the regions of interest.

[0183] Device Programming

[0184] In an exemplary embodiment of the invention, device 100 isprogrammed or otherwise controlled to provide a desired spatial and/ortemporal regimen to the heart. Such a regimen can define which part ofthe heart is treated with which molecule and/or electrical field forwhat duration and under what circumstances. Such programming may be donein advance of implantation and/or therapy or it may be provided intodevice 100 just before or during therapy. In some embodiments of theinvention, device 100 is used for experimental use, for example todetermine which electric fields and/or molecules and/or combinationsthereof have desirable therapeutic effects. Such a determination may beapplied during product design or even when planning a therapeutic planfor a patient, as described herein.

[0185] Programming input 136 (FIG. 2) may be used for providing inputfrom an external programmer. Device 100 may be non-autonomous, in thatall programming comes from outside. Alternatively, a semi-autonomousdevice may be provided, in which external programming is required onlyon occasion, possibly at the instigation of device 100.

[0186] As can be appreciated, different transport fields and/ordifferent molecules may be used for different heart rates, strokevolumes and/or as a function of other cardiac parameters. Depending onthe desired effect of the molecule, the cardiac parameters taken intoaccount may be local parameters, such as conduction velocity or globalparameters, such as heart rate. The cardiac parameters may be rapidlychanging parameters, such as heart rate or they may be slowly changingparameters such as tissue performance, Perfusion and/or viability, ormaximum diastolic extension over a period of time. In some cases, theprogramming responds to non-cardiac parameters, such as time of day orday of the week, for example to match the therapy to an expected orcurrent activity level.

[0187] Various device parameters may be programmable, including, forexample, pulse parameters such as temporal, spatial, amplitude,polarity, envelope and/or frequency of the applied transport, transportrelated, excitatory (e.g., pacing) and/or non-excitatory fields.Alternatively or additionally, various molecule provision parameters maybe controllable, for example the molecule type, timing of provision,amount provided and duration. In some devices, a complete script (e.g. ashort program) may be selected or programmed. Alternatively oradditionally, script parameters may be selected. A particular example ofa script parameter is which sensor to use for monitoring and itsassociated threshold levels or other value-response function.

[0188] The programming may be enhanced by providing feedback about theoperation and effects of device 100. The information may be sensedand/or stored by device 100 for later readout by the programmer.Alternatively, the information may be gleaned using other physicalexamination techniques, for example medical imaging.

[0189] Exemplary types of feedback include one or more of: feedback onmolecule provision and penetration, various actually realized fields,the effect of such fields for transport or on cardiac tissue and/or theeffect of the provided molecule, on the local tissue, the heart and/orthe circulatory system as a whole. Alternatively or additionally,feedback on the quality and degree of synchronization between the heart,molecule provision and/or the various electrical fields, may bedesirable. Exemplary sensors are described below.

[0190] In an exemplary embodiment of the invention, feedback is providedwith regard to the penetration of the molecules. By using local sensingelectrodes, the arrival of the molecules at the desired tissue depth canbe monitored by detecting the effect of the molecules. Alternatively oradditionally, by transporting radioactive or other marker drugs, it ispossible to image or otherwise view the tissue and determine which cellswere affected. A marker drug may be the same as the one used for therapyor it may be a different one, specifically selected for ease ofdetection. Alternatively or additionally, the provision and/or effect ofmolecules may be detected by applying an electric field to the treatedarea and based on the response of the tissue estimate the moleculeeffect and/or arrival.

[0191] In some cases, real-time feedback is desired, either to controldevice 100 in operation or to adjust programming parameters based ontheir effect. It should be noted that different types of feedback may berequired for slow acting and for fast acting molecules. Some moleculesmay be double acting—having an effect that can be detected immediately,useful for verifying penetration and also having a long term effect.Fast acting molecules or drugs with a fast onset may require fastresponding sensors. Slow acting drugs or drugs with a gradual onset mayrequire sensors which average over several cardiac cycles and/or aprocessor associated with the sensor for processing the input therefrom.

[0192] One or more sensors (in some cases the field applicationelectrodes can double as sensors) may be used to provide an indicationof the heart's current status or its response to certain treatments.Exemplary sensors are described below. SENSORS

[0193] Various sensors may be used in conjunction with and/or as part ofdevice 100. Such sensors may measure various cardiac parameters,including, for example, pCO₂, pO₂pH, SO₂, wall motion, local or globalelectrical activity, endocardial acceleration, regional impedance,regional APD, HR variability, LVP or aortic pressures (peak, max dP/dt),respiration rate, cardiac output and/or thoracic impedance (forestimating changes in stroke volume). Many such suitable sensors areknown in the art. Alternatively or additionally, the sensors may measuresystemic parameters, such as blood pressure. Alternatively oradditionally, the sensors may measure local molecule concentrationsand/or metabolic products.

[0194] The sensors may be implanted in the body. Alternatively, in someembodiments, the sensors maybe outside the body, even if device 100 isinside the body.

[0195] In some embodiments of the invention, the patient himself servesas a sensor, for example indicating to device 100 or its externalprogrammer, body feelings, such as pain, shortness of breath, dizzinessand/or lack or abundance or energy.

[0196] Safety

[0197] In some exemplary embodiments of the invention, device 100 mayinclude one or more of the following safety features:

[0198] (a) Toxicology Watchdog.

[0199] This type of watchdog monitors one or more cardiac parametersand/or the response of the heart to various stimuli, to determine if thesupplied molecules have an adverse effect on the heart. As a result,protective measures, such as fencing, may be applied, or the dosage orother parameters of drug delivery may be modified.

[0200] (b) Defibrillation Circuit.

[0201] Upon detection of defibrillation and/or VT, this circuit canapply a defibrillation current to the heart. Such a defibrillator mayhave charged capacitors continuously available in a standby mode. Whennot required for fibrillation, some of the charge may be used forapplying large non-excitatory fields, for example for moleculetransport.

[0202] (c) Molecule Flow Monitor.

[0203] This monitor checks that the supply rate of the molecule matchesthe programmed supply rate. Thus, blockages and/or leaks may bedetected. The monitor may directly monitor the flow and/or the moleculereservoir state. Alternatively, the monitor may determine the supplyrate indirectly by analyzing cardiac and/or other patient physiologicalparameters.

[0204] (d) Fences.

[0205] Non-excitatory electric fields may be used to create fences inthe heart which prevent the propagation of undesirable (expected or not)activation potentials. Such field may act, for example, by desensitizingcardiac tissue using a DC field or by extending a refractory period ofthe cells by applying an electric pulse during an end of the refractoryperiod.

[0206] (e) Beat Capture.

[0207] Various pacing schemes may be applied to increase the capture ofthe heart rate by the pacing signal and to avoid certain types ofarrhythmia

[0208] Exemplary Applications

[0209] In one example, a heart is remodeled, by providing geneticmaterial or other molecules which cause certain parts of the heart toatrophy or enlarge. In another example, the activation of the heart ismodeled, for example by causing a cell type, such as an AV node cell, toincrease its conduction velocity, for example by suitableover-expression or under-expression of certain ion pumps or channels.Other cell parameters which may be changed using this method includesensitivity (to hormones electrical signals and/or other feedback loopsin the heart), plateau duration, excitation window duration andself-pacing rate (SA node).

[0210] In another example, at least certain types of long QT syndromepatients are treated by causing the expression of suitable ion channelsor pumps to those cells that require it. This expression can be causedby providing the gene that creates the channels or creates a proteinthat transports the channels to the cell membrane, as well as byblocking a gene which stops the production of the channel.

[0211] In a post ischemic-event treatment application, drugs formaintaining the dilation of blood vessels or drugs for reducing oxygenrequirements may be applied. In addition, molecules damaged or destroyedby the ischemic event may be provided by electrical transporttechniques.

[0212] In an angiogenesis application, hormones and/or otherangiogenesis factors are electrically transported to ischemic tissueand/or other tissue in the heart to cause increased blood vesselgeneration. In a particular application, repeated transport pulses,possibly from different electrodes are used to maintain a particularvolume distribution of the provided molecule(s). In one example, thesemolecules define a gradient along which blood vessels or other tissuegrow, or various cells, such as lymphocytes, travel. In another example,this distribution defines an area into which new growth will not enter.

[0213] In a related application, VEGF and/or other growth factors arelocally provided, to prevent their adverse effects on other parts of theheart and/or body.

[0214] In another exemplary application, a locally provided molecule isAdriamycin or other chemotherapy anti-cancer molecules.

[0215] In a slow ablation application, a drug which suspend activity ofa heart cell is applied to points of a mesh electrode. After detectingthe effects of suspension on the electrical activity of the heart, anelectrode having a desired effect is used to provide a killing dose ofthe same drug or of a different drug. Alternatively, selective ablationis possible even without first determining the effect of a “suspending”drug.

[0216]FIG. 6 illustrates a vascular treatment device 800, in accordancewith an exemplary embodiment of the invention. In a coronary vesselapplication, iontophoresis and electroporation become possible in bloodvessels which are near the heart. Example treatments includeanti-clotting drugs, drugs to prevent re-stenosis, drugs to preventstenosis and gene therapy to convert the blood vessel cells to thosehaving a desired function, such as excretion of a desired anti-clottingfactor. Such an the electric field may be applied using a dedicatedsuitable stent or to augment the behavior of a stent which needs to beimplanted. Exemplary device 800 is stent-like, having a cylindrical body802. A plurality of electrodes 804 and 806 are provided, which areelectrified by a power supply 810. In one embodiment of the invention,the power supply is a battery. Alternatively or additionally, the powersupply comprises an antenna 812 for receiving RF radiation and aconverter for converting the received radiation in suitable voltages.Alternatively or additionally, power supply 810 include control logicand/or one or more sensors, for example for sensing a cardiac activity,for example for synchronization purposes or a sensor for sensing theblood vessel state. Optionally, electrodes 804 and 806 can serve asantenna 812. Alternatively, a wired external power source is providedand connected to device 800. In some embodiments, device 800 is usedwith blood vessels not adjacent to the heart. In some embodiments of theinvention, antenna 812 also serves to apply a voltage across the vesselin which device 800 is situated.

[0217] An exemplary configuration for transmitting power by RFradiation, to a stent-like device, which may store the energy in acapacitor, is shown in PCT publication WO 99/55360 to Medtronic, et al.,the disclosure of which is incorporated herein by reference. The actuallevels of power and/or voltage required in device 800 may be higher,possibly requiring a straightforward design modification and/or avoltage converter in device 800. RF radiation may also be used to sendcommands to device 800.

[0218] In an exemplary embodiment of the invention, a molecule reservoir808 is provided between two adjacent electrodes, for example on anoutside surface of body 802. When a voltage potential is formed betweenelectrode 804 and electrode 806, the molecule is transported fromreservoir 808. The molecule may then diffuse into a surrounding wall ofa blood vessel. Alternatively or additionally, the voltage field betweenthe electrodes has a sufficient component to transport the moleculeperpendicular to device 800. Alternatively or additionally, the voltagefield opens pores in the vessel wall to enhance the diffusion of themolecule.

[0219] In an alternative embodiment, device 800 comprises two or morelayers, with one polarity electrode in one layer and a second polarityelectrode in the other layer.

[0220] In another alternative embodiment, device 800 is mounted outsidethe blood vessel. In such a case, a cylindrical body shaped like body802 in the figure may not be required, so wireless patch-shapedelectrodes may be provided instead.

[0221] In another exemplary embodiment, a work increasing excitatory(e.g., over pacing) or non-excitatory (e.g., contractility enhancing)pulse is applied to provide oxygen stress, while, at a same time,angiogenesis enhancing molecules are provided, locally or systemically.

[0222] In another exemplary embodiment, the salvage of ischemia-damagedtissue is enhanced by both reducing its oxygen requirements using adesensitizing electric field (or fences) and by locally providingwork-reducing molecules, such as calcium blockers. In some embodiments,the calcium blockers are systemically provided in a form that hasdifficulty crossing blood vessel walls. By application of a local field,the calcium blockers affect substantially only the treated area. In somecases, the molecule and the electric field are applied simultaneously.In other cases, they are alternated, for example to allow the tissue torecuperate from adverse effects of one or the other. Once the tissue hassufficiently recuperated, it may be trained back to shape and/or haveangiogenesis enhancing methods applied to it.

[0223] In another exemplary embodiment, hypertrophy of a part of theheart is treated by applying a suitable electrical control sequence toreduce the cardiac activity of the part and applying a molecule toreduce the hypertrophy.

[0224] Circulating Reservoir

[0225] In an exemplary embodiment of the invention, the device is usedto release a molecule from a circulating reservoir. In an exemplaryembodiment of the invention, the device is stent-like, for example asshown in FIG. 6. Alternatively, the device may comprise electrodesinside or outside the blood vessel.

[0226] In an exemplary embodiment of the invention, the reservoircomprises a plurality of liposomes that encapsulate a molecule.

[0227] U.S. Pat. No. 6,041,252 to Walker et al., the disclosure of whichis incorporated herein by reference, describes liposome compositions andfield strengths that will cause the liposomes to release their contentsand/or migrate towards the walls of a blood vessel. Also described is anon-toxic material for sealing temporary pores formed in body cells as aresult of the applied field. Also described are various therapeuticmaterials. Alternatively or additionally, non-electrical means may beused to free the molecule from the liposome, for example, chemical meanssecreted by the device into the blood flow, for example Nystatin thatforms pores in liposomes, special molecules for liposomes designed to beopened by chemical means and/or other means, such as heating means, oroptical means, for suitably sensitive liposomes.

[0228] Referring back to FIG. 6, device 800 may include electrodes forapplying a field across the blood vessel, to release molecules from acirculating reservoir, alternatively or additionally, to applying aniontophoresis field, an electrophoresis field and/or a field forreleasing a molecule from reservoirs 808. The electrification of theelectrodes and/or their layout may be different for the differenteffects, for example for liposome release or migration, differentpolarity electrode elements may be provided on opposite sides of device800, so that the field is applied across the blood vessel. Forextraction from reservoir 808, a voltage between two nearby electrodesmay be applied. In an exemplary embodiment of the invention, electrodes804 and/or 806 comprise multiple parts, which can be selectivelyelectrified to achieve various field directions and/or strengths underthe control of controller 810.

[0229] A sensor in device 800 may be used to synchronize the applicationof the release and/or transport fields to local and/or global activityof the excitable tissue. Alternatively, other effects can be achieved bythe fields, as described above. The transport field, the release filedand the control filed may be the same or different fields and/or twoeffects may be combined in a single field.

[0230] In an exemplary embodiment of the invention, device 800 is usedto release molecules in the vascular bed of an organ to be treated, forexample in a coronary artery of the heart or a renal artery.Alternatively or additionally, the molecules are released into a vesselthat passes near the tissue to be treated. Alternatively oradditionally, the molecules are released in the vessel, to betransported, (e.g., electrically) through the vessel walls into nearbytissue.

[0231] Reservoir 808, or multiple reservoirs, may include a samemolecule or different as in the circulating reservoir. Alternatively oradditionally, multiple reservoirs with different materials may beprovided. Optionally, non-electrical release from reservoir 808 is used.At least one or the reservoirs in device 800 may be pointed inwards, torelease its contents into the blood stream. Alternatively oradditionally, it may be pointed outwards, to release its contents intothe vessel wall. Alternatively or additionally, the release directionmay be controlled by the particular transport electric field applied. Ina non-stent device, the reservoir may be provided and/or activatedseparately from the electrodes.

[0232] In an exemplary embodiment of the invention, the locally releasedmolecule may interact with a systemically available molecule. In oneexample, the locally available molecule is an antagonist for thesystemic molecule, so that the systemic molecule has a different or noeffect locally (e.g., Heparin and its antagonist Protamine).Alternatively or additionally, the systemic molecule prevents the localmolecule from having an effect away from where it is released, forexample, due to the lower concentration of the local molecule.Alternatively, an enhancement effect may be provided, with the localmolecule enhancing or activating the systemic molecule, or vice versa.The systemic molecule may be provided as a circulating reservoir or byinjection or other means. Thus, in some embodiments of the invention,the systemic molecule is released locally, together with another locallyreleased molecule from device 800.

[0233] In another example, device 800 is used to genetically modify(e.g., by eluting viruses or direct electrophoresis of DNA) the vasculartissues. These modified tissues may elut a chemical that interacts withthe systemic drugs (or otherwise provided molecule). Alternatively oradditionally, the modified cells may include fewer or a greater numberof receptors (or other reason for sensitivity) for the systemic drug.Alternatively or additionally, the modified cells may exhibit a higheror lower uptake or transport rate for the drug.

[0234] In an exemplary embodiment of the invention, two sensors areprovided, one at the entrance to the targeted tissue and one at adifferent location, for example elsewhere in the vascular system or atthe vascular exit from the targeted tissue. The second sensor, which mayalso be mounted on a stent, possibly a molecule releasing stent, maymeasure the amount of the released molecule in the blood stream. Themeasurement may be direct, or a easily detectable tag may be releasedwith the molecule.

[0235] Such measurement may be applied during testing of dosage orduring calibration or regular use of device 800. For example, the seconddevice may indicate to the user that the level of circulating moleculeis too high (or too low). Alternatively or additionally, the seconddevice may automatically elute an antagonist to the molecule secreted bythe first device. Optionally, such automatic secretion is performedwithout a sensor, for example, based on calibration of the device or byexternal activation.

[0236] Non-Cardiac Applications

[0237] The above application has focused on cardiac applications. Itshould be noted that similar devices may be used for non-cardiacapplications, in whole organs or in portions of excitable ornon-excitable tissues. It should be noted that the heart typically hastwo properties not found in other excitable tissue: synchronousoperation and significant and immediate health risk due to adverseeffects. The brain for example, as a whole, does not exhibit unitarysynchronized behavior as does the heart. The stomach on the other hand,while it is synchronous, does not pose immediate life-threatening dangeras a result of adverse effects. However, many non-cardiac tissue maycause discomfort (sort or long term) and/or pain, if incorrectlyactivated. Thus, in some cases, an excitatory transport or release pulsemay be used. Alternatively or additionally, the electric fields appliedare synchronized to the activation in the excitable tissue.Alternatively or additionally, a propagation stopping field (fencing)may be used to prevent propagation of the effects of the transportpulse.

[0238] It should be noted that some excitable tissues may be relaxed byapplication of a suitable non-excitatory or excitatory pulse, thuspossibly assisting transport. Alternatively or additionally, the pulsemay target excitable components of the tissue, for example bloodvessels. Alternatively or additionally, the electric field may beapplied to stiffen excitable tissue, thus preventing molecule uptake.

[0239] In some embodiments of the invention, the application ofelectrical field and/or molecules ignores the excitatory (or excitationdisruption) effect of the electric field, but uses other featuresdescribed herein, for example multiple vectored molecule distributionusing electrode arrays, reduction of blood flow or implantable wirelesselectrodes having associated therewith molecule reservoirs.Alternatively, non-pain causing effects, such as muscle contractions, oreven pain causing effects, such as muscle spasms may be ignored or takeninto account when applying the fields. It is noted that also somecardiac applications can allow the transport field to be excitatory.,One exemplary application is treatment of irritable bowel syndrome usinglocally transported anti-inflammatory drugs, such as steroids. The drugsand/or a transport-related signal possibly timed to the normal bowelelectrical activity so as not to interfere with it. Alternatively oradditionally, the electrical signal also controls the bowels. For boweland other hollow organ applications, a device similar to that of FIG. 6may be used. In an exemplary embodiment of the invention, the drugs arereleased in the upper or lower mesenteric arteries, to better targetthem to the bowels. Alternatively or additionally, a systemic inhibitoris provided, to reduce the effect of the drugs on tissues outside of thebowels.

[0240] In a pulmonary application, COPD and asthma are treated, forexample, using adrenergic agonists, phosphodiesterase inhibitors,steroids and/or cholinergic antagonists. The electric fields may beselectively applied to prevent inadvertently affecting the heart.

[0241] In a urinary example, muscle relaxants to bladder are locallyprovided, for example at night, to treat overflow incontinence caused byan over excited bladder. A suitable implantable device may be, forexample, a stent implanted inside the urethra. Local provision mayprevent possibly systemic and/or organ specific side effects of smoothmuscle relaxants, for example, hypotension, digestive problems and/orcardiac effects.

[0242] In a joint application, gold or other lubricants are transportedinto a joint, for example with the electric field synchronized toprevent inadvertent electrical activation of muscles.

[0243] In a non-cardiac angiogenesis application, the growth of newvessels in an organ is provided by targeting VEGF (or other growthfactors) to that organ or part thereof, for example, to combat orprevent diabetes-related gangrene.

[0244] In a uterine application, uterine contractions are suppressedduring labor, or during an early labor, using targeted tocolytic drugsand/or suitable electrical pulses. Alternatively, contractions areenhanced and/or controlled while and/or shortly after providing a drug.Optionally, the uterus is relaxed when the drug is provided, to assistin tissue penetration. Alternatively or additionally, the uterus may becontacted after the provision, to enhance delivery.

[0245] In a skeleton muscle example, muscle relaxants may be supplied,locally to a muscle limb and/or a part thereof.

[0246] Targeted Protection

[0247] In an exemplary embodiment of the invention, protection of anorgan from a system effect is supplied by providing, at a vascularentrance to organ, a device that releases antagonist molecules. Therelease may be synchronized to the availability of systemic molecules,for example, both being controlled by a same controller. Any type ofrelease mechanism may be used, including electrical and non-electricalmechanisms. In a particular example, the kidney is protected fromcyclosporine, an anti-rejection drug, which may provided for preventingrejection of an implanted heart.

[0248] Alternatively or additionally, the system may be protected from amolecule targeted to a particular tissue, for example, by releasing theantagonist at the vascular exit from the tissue. For example, anantagonist for a cardiac stimulator, at the exit from the coronaryvessels. Alternatively or additionally to chemical antagonists,antibodies may be used for tagging and/or activity prevention. Taggingmay be used for collecting information about dosages and its effectsand/or for stimulating removal by the pagocytic system.

[0249] In another example, a suitable antagonist is used to counteracttoxic effects of a molecule used to release a drug from a liposome.

[0250] In another exemplary embodiment of the invention, a systemic.,less active molecule is provided, with an activator being released at avascular entrance to an organ and/a deactivator being released at thevascular exit from the organ.

[0251] Multi-Treatment Kit

[0252] In an exemplary embodiment of the invention, the device (e.g.,device 800) is provided as a kit that may be used with a variety ofmolecules, organs, treatment protocols and/or systemic provisionprotocols. The kit may include, for example, a stent and an externalcontroller, for providing programming of the stent and/or real-timecontrol of the stent. Optionally, such a kit includes multiple stents,for example for providing an activator/deactivator pair of molecules.

[0253] In some embodiments, a multi-catheter system is used to providemultiple types of molecules and/or multiple electrode locations.

[0254] It will be appreciated that the above-described methods oftransporting molecules in the various tissues may be varied in manyways. In addition, a multiplicity of various features, both of methodsand of devices has been described. Where methods are described, devicesfor carrying out the methods are also contemplated. It should beappreciated that different features may be combined in different ways.In particular, not all the features shown above in a particularembodiment are necessary in every similar exemplary embodiment of theinvention. Further, combinations of the above features are alsoconsidered to be within the scope of some exemplary embodiments of theinvention. Also within the scope of the invention are devices and/orsoftware for programming existing devices to make the device comply withthe methods described herein. Section headings where they appear aremeant for clarity of browsing only and should not be construed aslimiting the contents of a section to that particular section. When usedin the following claims, the terms “comprises”, “includes”, “have” andtheir conjugates mean “including but not limited to”.

[0255] It will be appreciated by a person skilled in the art that thepresent invention is not limited by what has thus far been described.Rather, the scope of the present invention is limited only by thefollowing claims.

1. Electrical treatment apparatus for use with an associated moleculesource, comprising: at least one electrode; a power source forelectrifying said at least one electrode; and a controller, which isprogrammed to activate the power source to selectively electrify said atleast one electrode to apply at least one electric field including atransport effect for transporting a molecule in a desired manner and anon-excitatory control effect for controlling the activity of at least apart of a non-cardiac excitable tissue, said programming selected toachieve a desired provision of said molecule into said at least a partof an excitable tissue or associated vasculature, said desired provisionbeing at least assisted by an interaction between the transport effectand the control effect.
 2. Apparatus according to claim 1, wherein saidcontroller is hardware programmable.
 3. Apparatus according to claim 1,wherein said controller is software programmable.
 4. Apparatus accordingto claim 2 or claim 3, comprising a wireless programming input. 5.Apparatus according to any of claims 1-4, wherein said programmingcomprises programming adapted for said patient.
 6. Apparatus accordingto any of claims 1-5, wherein said programming comprises a setting of atleast one operational parameter of said apparatus.
 7. Apparatusaccording to any of claims 1-6, wherein said programming comprises aselection or at least, one operational protocol from a set of availableprotocols in said apparatus.
 8. Apparatus according to any of claims1-7, wherein said controller is operable in a testing mode, in whichmode a test treatment of a molecule is provided to the patient and theresponse of the patient to the test is monitored by said controller. 9.Apparatus according to any of claims 1-8, comprising a synchronizationconnection to a molecule source containing said at least one type ofmolecule.
 10. Apparatus according to claim 9, wherein saidsynchronization connection comprises an informative connection thatprovides at least one informative signal to said controller, informingof a state of molecule release.
 11. Apparatus according to claim 9 orclaim 10, wherein said synchronization connection comprises a controlconnection that provides at least one control signal from saidcontroller, to control a state of molecule release.
 12. Apparatusaccording to claim 11, wherein said molecule source is an electric-fieldmediated molecule source and wherein said control signal generates anelectric field that releases said molecule from said source. 13.Apparatus according to claim 12, wherein said synchronization connectionis comprised in said at least one electrode used for applying atransport effect.
 14. Apparatus according to claim 13, wherein saidmolecule source is integral with said electrode.
 15. Apparatus accordingto claim 13, wherein said molecule source comprises blood dispersedmolecules.
 16. Apparatus according to any of claims 1-11, wherein saidmolecule source is integral with said at least one electrode used forapplying a transport effect.
 17. Apparatus according to any of claims1-11, wherein said molecule source is integral with said apparatus. 18.Apparatus according to any of claims 1-11, wherein said molecule sourceis external to said apparatus.
 19. Apparatus according to any of claims1-11, wherein said molecule source comprises a catheter, coupled to saidapparatus outside said patient.
 20. Apparatus according to any of claims1-11, wherein said molecule source comprises a source of a plurality ofmolecule types.
 21. Apparatus according to claim 20, wherein saidcontroller controls said molecule source to selectively release at leasta particular one of said plurality of molecule types.
 22. Apparatusaccording to any of claims 1-21, comprising at least one sensor thatsenses a functional tissue parameter and provides said sensed parameterto said controller.
 23. Apparatus according to claim 22, wherein saidsensor measures a functional tissue parameter relating to the entireexcitable tissue.
 24. Apparatus according to claim 22, wherein saidsensor measures a functional tissue parameter relating to a portion ofthe excitable tissue.
 25. Apparatus according to any of claims 22-24,wherein said controller analyses said sensed parameter to detect aneffect of said molecule on said excitable tissue.
 26. Apparatusaccording to any of claims 22-24, wherein said controller analyses saidsensed parameter to detect an activity of the excitable tissue andwherein said controller synchronizes said provision to said sensedactivity.
 27. Apparatus according to any of claims 22-24, wherein saidcontroller analyses said sensed parameter to detect an effect of saidtransport field on said excitable tissue.
 28. Apparatus according to anyof claims 22-27, wherein said controller modifies said at least oneelectric field to modify said transport effect responsive to said sensedparameter.
 29. Apparatus according to any of claims 22-27, wherein saidcontroller modifies said at least one electric field to modify saidcontrol effect responsive to said sensed parameter.
 30. Apparatusaccording to any of claims 22-29, comprising a watchdog that detects anabnormal effect of said applied fields.
 31. Apparatus according to anyof claims 22-30, comprising a watchdog that detects an abnormal effectof said molecule.
 32. Apparatus according to any of claims 1-31,comprising a user input for receiving an indication of an effect of saidapparatus from said patient.
 33. Apparatus according to any of claims1-32, wherein a single electric field applies both of said transporteffect and said control effect.
 34. Apparatus according to any of claims1-32, wherein said at least one electric field comprises at least onetransport field and at least one control field.
 35. Apparatus accordingto any of claims 1-34, wherein said transport effect and said controleffect are provided simultaneously.
 36. Apparatus according to any ofclaims 1-34, wherein said transport effect and said control effect areapplied sequentially.
 37. Apparatus according to any of claims 1-34,wherein said control effect is selectively applied in association withonly some of said transport effects.
 38. Apparatus according to any ofclaims 1-37, comprising at least one pacing electrode that is controlledby said controller to apply a pacing pulse.
 39. Apparatus according toclaim 38, wherein said at least one pacing electrode is comprised insaid at least one electrode.
 40. Apparatus according to any of claims1-39, wherein said transport effect is provided by an excitatory field.41. Apparatus according to any of claims 1-39, wherein said transporteffect is provided by a non-excitatory field.
 42. Apparatus according toany of claims 1-41, comprising an output port for generating an outputto said patient.
 43. Apparatus according to any of claims 1-42, whereinsaid control effect is selected to prevent an adverse effect of saidtransport pulse.
 44. Apparatus according to any of claims 1-43, whereinsaid control effect is selected to prevent an adverse effect of saidmolecule.
 45. Apparatus according to any of claims 1-44, wherein saidmolecule is selected to counteract an adverse effect of said controleffect.
 46. Apparatus according to any of claims 1-45, wherein saidcontrol effect is selected to counteract an adverse effect of saidmolecule.
 47. Apparatus according to any of claims 1-46, wherein saidcontrol effect is selected to prepare said tissue for said transport.48. Apparatus according to any of claims 1-47, wherein said controleffect is selected to extend a period of time suitable for provision ofsaid molecule.
 49. Apparatus according to any of claims 1-48, whereinsaid control effect and said molecule are selected to cooperate andeffect a desired treatment of said tissue.
 50. Apparatus according toany of claims 1-49, wherein said at least one electrode comprises atleast one transport electrode for applying a transport effect of said atleast one field and at least one control electrode for applying saidcontrol effect of said at least one field.
 51. Apparatus according toany of claims 1-49, wherein said transport effect and said controleffect of said at least one electric field are applied using at leastone common electrode of said at least one electrode.
 52. Apparatusaccording to claim 50, wherein said at least one control electrode isspatially displaced from said at least one transport electrode. 53.Apparatus according to any of claims 1-52, wherein said at least oneelectrode comprises a point electrode.
 54. Apparatus according to any ofclaims 1-52, wherein said at least one electrode comprises a spiralelectrode.
 55. Apparatus according to any of claims 1-52, wherein saidat least one electrode comprises a linear electrode.
 56. Apparatusaccording to any of claims 1-52, wherein said at least one electrodecomprises a mesh electrode.
 57. Apparatus according to any of claims1-52, wherein said at least one electrode comprises a plate electrode.58. Apparatus according to any of claims 55-57, wherein said electrodecomprises a plurality of independently electrifiable contacts. 59.Apparatus according to claim 58, wherein said controllers selectivelyelectrifies said independent contacts to achieve a desired, non-uniform,volumetric dispersion of said molecule, relative to said electrode. 60.Apparatus according to any of claims 1-59, wherein said at least oneelectrode is connected by wire to said controller.
 61. Apparatusaccording to any of claims 1-59, wherein said at least one electrode isa wireless electrode.
 62. Apparatus according to any of claims 1-61,wherein said at least one electrode is implantable.
 63. Apparatusaccording to any of claims 1-61, wherein said at least one electrode ismounted on a catheter.
 64. Apparatus according to any of claims 1-61,wherein said at least one electrode is an external electrode. 65.Apparatus according to any of claims 1-61, wherein said apparatus isimplantable.
 66. Apparatus according to any of claims 1-61, wherein saidapparatus is comprises in a cylindrical body adapted for implantationinside a blood vessel.
 67. Apparatus according to any of claims 1-61,wherein said apparatus is wholly external to the patient.
 68. Apparatusaccording to any of claims 1-67, wherein said transport effect comprisesiontophoresis.
 69. Apparatus according to any of claims 1-68, whereinsaid transport effect comprises electroporation.
 70. Apparatus accordingto any of claims 1-69, wherein said non-cardiac excitable tissuecomprises uterine tissue.
 71. Apparatus according to any of claims 1-69,wherein said non-cardiac excitable tissue comprises bladder tissue. 72.Apparatus according to any of claims 1-69, wherein said non-cardiacexcitable tissue comprises digestive tissue.
 73. Apparatus according toany of claims 1-69, wherein said transport effect comprises releasing amolecule from a circulating reservoir.
 74. Apparatus according to claim73, wherein said circulating reservoir comprises liposomes in a bloodstream.
 75. Apparatus according to any of claims 1-74, wherein saidcontroller coordinates the interaction of a systemic molecule andlocally available molecule, to have a synergistic effect.
 76. Apparatusaccording to claim 75, wherein said local molecule blocks an effect ofsaid systemic molecule.
 77. Apparatus according to claim 75, whereinsaid local molecule enhances an effect of said systemic molecule. 78.Apparatus according to claim 75, wherein said systemic molecule blocksan effect of said local molecule away from said a locality where saidlocal molecule is provided.
 79. Apparatus according to claim 75, whereinsaid systemic molecule enhances an effect of said local molecule. 80.Electrical treatment apparatus for use with an associated moleculesource, comprising: at least one electrode; a sensor for sensing afunctional state of a non-cardiac tissue; a power source forelectrifying said at least one electrode; and a controller, which isprogrammed to activate the power source to selectively electrify said atleast one electrode to apply at least one electric field including atransport effect for transporting a molecule in a desired manner,synchronized to said sensed functional state.